1. Field of the Invention
The present invention relates to a process for the preparation of 1-alkylisoquinoline derivatives, in particular, 1-alkyl-1,2,3,4-tetrahydroisoquinolines and 1-alkyl-1,2-dihydroisoquinolines in which the alkyl radicals in the 1-position can also be substituted.
2. The Prior Art
The 1-alkylisoquinoline structure is the basic building block for various pharmaceutically active compounds, such as antihypertensives of the salsoline type, spasmolytics of the papaverine type or analgesics of the morphine type. Derivatives of 1-alkylisoquinoline are, therefore, useful intermediates for the preparation of active compounds of this type.
A plurality of processes are known for the preparation of 1-alkylisoquinolines in which starting either from a .beta.-phenylethylamine and subsequent acylation of the amino group, the ring closure to the isoquinoline is carried out in the presence of acids, at elevated temperature, and known in the literature under the name "Bischler-Napieralski cyclization." 3,4-dihydroisoquinolines are formed here.
In the condensation of .beta.-phenylethylamines with carbonyl compounds in acidic solution, the ring closure to the isoquinoline takes place by intramolecular aminomethylation, which is known in the literature as "Pictet-Spengler cyclization." 1,2,3,4-tetrahydroisoquinolines are formed here.
A third route for the preparation of isoquinoline derivatives in which aromatic aldehydes are condensed with aminoacetals, and the iminoacetals thus obtainable are then cyclized by the action of acid, which is known in the literature as "Pomeranz-Fritsch cyclization", is virtually impractical for the preparation of 1-substituted isoquinoline derivatives, such as 1-benzylisoquinoline derivatives, as the corresponding aromatic ketones are not only accessible with difficulty, but these also react with aminoacetals only with difficulty, or not at all. Moreover, the subsequent cyclization of benzylaminoacetals under acidic conditions leads virtually exclusively to the formation of the undesired isopavine or pavine structure [see, "Tetrahedron," S. F. Dyke et al, Vol 22, p. 3803 et seq. (1971)].The cyclization of benzylaminoacetals can only be carried out preparatively after acylation of the nitrogen; 1,2-dihydroisoquinolines are formed here [see, Chem. Pharm. Bulletin, Vol 30, K. Yamada et al, p. 3197 et seq. (1982)].
In order to avoid the disadvantages in the preparation of 1-substituted isoquinoline derivatives according to Pomeranz-Fritsch, the corresponding 1-unsubstituted isoquinoline derivatives can first be prepared and from these, by reaction with benzoyl chloride in the presence of potassium cyanide, 1-cyano-2-benzoyl-1,2-dihydroisoquinolines can be prepared. By reaction with benzyl chlorides and hydrolysis under alkaline conditions, which is known in the literature as "Reissert synthesis," the corresponding 1-benzylisoquinoline derivatives can be obtained therefrom [see, G. Blasko et al., Academic Press, Inc., The Alkaloids, Vol. 31, p. 1, et seq., (1987)].
The desired 1-alkylisoquinoline derivatives are, in general, produced by the processes mentioned in the form of racemates. Enantioselective syntheses, however, are also known. Thus, for example, an asymmetric total synthesis of (+)-reticuline was described, which starts from a 1-unsubstituted 1,2,3,4-tetrahydroisoquinoline derivative which is accessible by one of the reactions described above. The key step of this synthesis is the deprotonation of the 1,2,3,4-tetrahydroisoquinoline with tert-butyllithium at -78.degree. C. and the subsequent enantioselective alkylation of the 1-lithio-1,2,3,4-tetrahydroisoquinoline derivative at -100.degree. C., using an appropriately substituted benzyl bromide. Asymmetric induction is, in this case, executed by chiral formamidine. After this 5-step synthesis, (+)-reticuline was obtained, starting from the appropriately substituted phenylethylamine, in 98.6% ee (enantiomeric excess) and in a total yield of about 30% [see, Heterocycles, A. I. Meyers et al, Vol 28, p. 295, et seq. (1989)].
These known isoquinoline syntheses are, in general, multistep, and therefore uneconomical for carrying out on an industrial scale. In particular, the Pomeranz-Fritsch synthesis, by which 1-unsubstituted isoquinolines are relatively easily accessible, necessitates additional measures for the synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines and is, therefore, particularly complicated and time-consuming. Moreover, the insertion of enantioselective synthesis steps necessitates considerable outlay.